Vascular pharmacology

Thyroid hormone and angiogenesis.

PMID 19879961


In models of thyroid hormone-induced cardiac hypertrophy, there is appropriate, supportive angiogenesis. Twenty years ago in one such model, angiogenesis in response to the hormone was observed before hypertrophy developed and it is now understood that iodothyronines induce neovascularization in a variety of settings, including the heart, ischemic striated muscle and tumor beds. The molecular mechanism of the proangiogenic action of thyroid hormone is both nongenomic and genomic. It is initiated nongenomically at the cell surface receptor for the hormone on integrin alphavbeta3. Kinase transduction of the hormone signal and, ultimately, transcription of several anagiogenesis-relevant genes result. The genes include basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). In addition, the integrin receptor for thyroid hormone (l-thyroxine, T(4), and 3, 5, 3'-triiodo-l-thyronine, T(3)) engages in crosstalk with the VEGF and bFGF receptors. Occlusion with tetraiodothyroacetic acid (tetrac) of the hormone receptor on the integrin in the absence of T(4) and T(3) suppresses the angiogenic effects of VEGF and bFGF. Tetrac also blocks the proangiogenic actions of T(4) and T(3). Other thyroid hormone analogues that are angiogenic include diiodothyropropionic acid (DITPA) and the nuclear thyroid hormone receptor-beta-selective agonist, GC-1. Thyroid hormone sustains angiogenesis and coronary blood flow about infarcted heart tissue in experimental models and blocks deleterious heart remodeling that otherwise is predictable in such tissue. The hormone may also induce expression of the hypoxia-inducible factor 1alpha (HIF1alpha) gene, a transcription factor important to coronary artery collateralization in the setting of hypoxia. The hormone also causes transcription of the matrix Gla protein (MGP) gene that opposes vascular smooth muscle calcification.

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3,3′,5,5′-Tetraiodothyroacetic acid